Insulin-like growth factor (IGF-I) is a 7.5-kD polypeptide that circulates in plasma in high concentrations and is detectable in most tissues. IGF-I is predominantly a mitogenic factor for a variety of cell and tissue types, but also stimulates cell differentiation and cell proliferation. The importance of IGF-I to growth of tissues is suggested by increasing plasma concentrations throughout adolescence, reaching a plateau in adults, and in the requirement of most mammalian cell types for IGF-I for sustained proliferation. For a review of the wide variety of cell types for which IGF-I/IGF-I receptor interaction mediates cell proliferation, see Goldring, M. B. and Goldring, S. R., Eukar. Gene Expression, 1:31-326 (1991).
In vivo, serum levels of IGF-I are dependent on pituitary growth hormone(GH). Although the liver is a major site of growth hormone-dependent IGF-I synthesis, recent work indicates that the majority of normal tissues also produce IGF-I. A variety of neoplastic tissues may also produce IGF-I. Thus IGF-I may act as a regulator of normal and abnormal cellular proliferation via autocrine or paracrine, as well as endocrine mechanisms.
The first step in the transduction pathway leading to IGF-I-stimulated cellular proliferation is binding of receptor ligand (IGF-I, IGF-II, or insulin at supraphysiological concentrations) to IGF-I receptor. The IGF-I receptor is composed of two types of subunits: an alpha subunit (a 130-135 kD protein that is entirely extracellular and functions in ligand binding) and a beta subunit (a 95-kD transmembrane protein, with transmembrane and cytoplasmic domains). The IGF-I receptor is initially synthesized as a single chain proreceptor polypeptide which is processed by glycosylation, proteolytic cleavage, and covalent bonding to assemble into a mature 460-kD heterotetramer comprising two alpha-subunits and two beta-subunits. The beta subunit(s) possesses ligand-activated tyrosine kinase activity. This activity is implicated in the signaling pathways mediating ligand action which involve autophosphorylation of the beta-subunit and phosphorylation of IGF-I receptor substrates.
Thus the IGF-I receptor is seen to play a pivotal role in normal and abnormal proliferative processes. Enhanced IGF-I levels are correlated with several, diverse pathological states, including acromegaly, gigantism. Abnormal IGF-I/IGF-I receptor function has been implicated in psoriasis, diabetes (microvascular proliferation), smooth muscle restenosis of blood vessels following angioplasty. In a variety of cancers, such as leukemia, lung cancer, ovarian cancer and prostate cancer, there is overexpression of the IGF-I receptor by the tumor tissue relative to the non-cancerous tissue, possibly implicating IGF-I/IGF-I receptor interaction in an autocrine or paracrine feedback loop resulting in autonomous proliferation of the tissue. For a review of the role IGF-I/IGF-I receptor interaction plays in the growth of a variety of human tumors, see Macaulay, V. M., Br. J. Cancer, 65: 311-320 (1992).
Potential strategies for the inhibition of cell proliferation associated with such pathologies include suppressing IGF-I levels or interrupting IGF-I action at the level of its cellular receptor. For example, drugs have been employed to reduce IGF synthesis and/or secretion. These include the long acting somatostatin analogue octreotide for treatment of endocrine tumors including carcinoid, and experimentally for the treatment of acromegaly and breast cancer, and tamoxifen for the treatment of breast cancer. However, there has been an inherent difficulty in suppressing circulating IGF-I to levels such that tissue concentrations become limiting to cell growth, especially without affecting normal growth of non-targeted tissue.
One strategy for interrupting IGF-I action at the level of its cellular receptor employs antibodies to the IGF-I receptor. However, it has been reported that these antibodies can be stimulatory rather than antagonistic over time. There is, therefore, a clear need in the art for methods of modifying ligand activated IGF-I receptor function at the cellular level. Preferably such methods would enable inheritable modifications of IGF-I receptor function in the cells of target tissue without disrupting the endogenous IGF-I receptor function in cells of nontargeted tissue.